Autoimmunity is thought to result from a combination of genetics, environmental triggers, and stochastic events. Although the role of environmental/xenobiotic agents in triggering autoimmunity is well established, it is unclear if idiopathic and experimentally induced disease arise by common genetic, molecular and cellular pathways. Genetic studies have suggested that idiopathic and xenobiotic-induced animal models of systemic autoimmunity share common requirements as well as significant differences, such as the importance of the inflammasome and type I interferons. The lack of genetic and phenotypic criteria for discriminating between idiopathic and environmental/xenobiotic-induced systemic autoimmune disease is a critical barrier to our understanding of autoimmunity in general. Inbred laboratory mouse strains have proven vital for autoimmune disease research because the inbred genotype provides a genetically uniform animal for experimental purposes. However, the restricted genetic heterogeneity among the common laboratory strains that is primarily derived from two original Asian and European fancy mice, limits the diversity of common variants that are currently thought to play the major role in complex diseases such as systemic autoimmunity. We propose that the Collaborative Cross (CC) mouse panel is better suited to model the range of phenotypes in complex disease because it is the only mammalian resource with genome-wide genetic variation randomized across a large, heterogeneous and reproducible population and it incorporates the genomes of three strains of wild mice from different continents. Consequently, CC mice strains provide a powerful tool to model environmental/xenobiotic-induced autoimmunity in a genetically heterogeneous population. To test this, we will examine the response of CC strains to crystalline silica and HgCl2. These two agents have been chosen because HgCl2 induces features of autoimmunity (autoantibodies, kidney disease), but not overt disease in humans and mice, while crystalline silica induces systemic autoimmune disease in both. We hypothesize that the genetic diversity of the CC panel of recombinant inbred (RI) strains will allow us to show that exposure to HgCl2 and silica leads to different profiles of immune mediators, inflammation, autoantibodies, and pathology which explain their disparate levels of disease severity. Additionally, we argue that use of the CC RI strains will not only significantly improve our ability to identify genetic loci, but to also determine specific genes and molecular pathways that discriminate HgCl2- and silica-induced systemic autoimmune disease from each other as well as from idiopathic systemic autoimmunity. We will address this in three aims. Specific aim 1: Analysis of baseline serum biomarkers in CC RI strains, Specific Aim 2: Induction and analysis of xenobiotic-induced autoimmunity in CC RI mice, and Specific Aim 3: Genetic mapping of xenobiotic-induced autoimmunity in CC RI mice. Successful completion of these studies should result in a greater understanding of the underlying genetics and biomarkers of xenobiotic-induced systemic autoimmunity, enhancing diagnostic capability, and identification of potential therapeutic targets.